Using a temperature-responsive micromold, MIT engineers created two-layer gel microparticles (the red and green areas represent separate layers). Photo: Halil Tekin |
Tiny
particles made of polymers hold great promise for targeted delivery of drugs
and as structural scaffolds for building artificial tissues. However, current
production methods for such microparticles yield a limited array of shapes and
can only be made with certain materials, restricting their usefulness.
In
an advance that could broadly expand the possible applications for such
particles, Massachusetts Institute of Technology (MIT) engineers have developed
a way to make microparticles of nearly any shape, using a micromold that
changes shape in response to temperature. They can also precisely place drugs
into different compartments of the particles, making it easier to control the
timing of drug release, or arrange different cells into layers to create tissue
that closely mimics the structure of natural tissues.
The
new technique, described in a paper published online in the Journal of the
American Chemical Society, also allows researchers to create microparticles
from a much more diverse range of materials, says Halil Tekin, an MIT graduate
student in electrical engineering and computer science and lead author of the
paper.
Currently,
most drug-delivering particles and cell-encapsulating microgels are created
using photolithography, which relies on ultraviolet light to transform liquid
polymers into a solid gel. However, this technique can be used only with
certain materials, such as polyethylene glycol (PEG), and the ultraviolet light
may harm cells.
Another
way to create microparticles is to fill a tiny mold with a liquid gel carrying
drug molecules or cells, then cool it until it sets into the desired shape.
However, this does not allow for creation of multiple layers.
The
MIT research team, led by Ali Khademhosseini, associate professor in the
MIT-Harvard Division of Health Sciences and Technology, and Robert Langer, the
David H. Koch Institute Professor, overcame that obstacle by building
micromolds out of a temperature-sensitive material that shrinks when heated.
The
mold is first filled with a liquid gel that contains one kind of cell or drug.
After the gel has solidified, the mold is heated so the walls surrounding the
solid gel shrink, pulling away from the gel and creating extra space for a
second layer to be added. The system could also be modified to incorporate additional
layers, Tekin says.
“The
method is quite creative,” says Michael Sefton, professor at the
University of Toronto Institute of Biomaterials and Biomedical Engineering, who
was not involved in this project. “It offers the opportunity to make
multilayer microstructures. The next step is figuring out what you can do with
these two-layer structures.”
Artificial tissue
So far, the researchers have created cylindrical and cubic particles, as well
as long striped particles, and many other shapes should be possible, Tekin
says. Their starting material was a gel made of agarose, a type of sugar.
The
long striped particles would be particularly useful for engineering elongated
tissues such as cardiac tissue, skeletal muscle, or neural tissue. In this study,
the researchers created striped particles with a first layer of fibroblasts
(cells found in connective tissue), surrounded by a layer of endothelial cells,
which form blood vessels. Researchers also created cubic and cylindrical
particles in which liver cells were encapsulated in the first layer, surrounded
by a layer of endothelial cells. This arrangement could accurately replicate
liver tissue.
Such
gels could also be embedded with proteins that help the cells orient themselves
in a desired structure, such as a tube that could form a capillary. The
researchers are also planning to create particles that contain collagen, which
constitutes much of the body’s structural tissues, including cartilage.
Eventually,
the researchers hope to use this technique to build large tissues and even
entire organs. Such tissues could be used in the laboratory to test potential new
drugs. “If you can create 3D tissues which are functional and really
mimicking the native tissue, they are going to give the right responses to
drugs,” Tekin says.
This
could speed up the drug discovery process and decrease the costs, because fewer
animal experiments would be needed, he says.
Filed Under: Drug Discovery
